DESCRIPTION: This project deals with the design, synthesis, pharmacological evaluations, and computational studies of non-competitive antagonists of the NMDA receptor. This application is mainly to synthesize compounds that are derived from PCP, which is itself a non-competitive antagonist of the NMDA receptor. The hypothesis behind this project is that appropriately substituted fluorine and hydroxy groups on the aromatic ring of PCP and its rigid analogs will lead to compounds that are selective for the non-competitive sites on NMDA receptors that will not significantly bind to sigma receptors. A corollary to this hypothesis is that a compound that is selective for NMDA receptors and which binds poorly to sigma receptors will not have psychotic effects.